"Study of the Effect of Low Level Laser in the Resolution of the Fibrotic Process in Chronic Kidney Disease"

Abstract

Chronic Kidney Disease (CKD) is recognized as a global public health problem. CKD is characterized by cellular infiltration into the kidneys, mainly macrophages, which produces growth factors and cytokines that lead to an imbalance between proliferation and apoptosis of tubular cells, promoting activation and proliferation of fibloblasts and consequently kidney fibrosis. The resolution of inflammation is a process orchestrated by endogenous mediators, receptors and ligands that stimulate the return of tissues to homeostasis thus preventing chronic inflammation and fibrosis (Serhan, 2009). During the resolution process, the major players include Lipoxins (e.g. LXA4), Annexin A1, Melanocortins, Resolvins, protectins and Adenosine. Pathological changes such as tubular cell atrophy and interstitial fibrosis are commonly seen in progressive renal disease, irrespective to initial etiology, representing the cardinal features of CKD (Nath KA, 1992; Remuzzi G, 1998). However, the molecular characteristics responsible for these pathological events remain to be fully understood. Microarrays analyses can be used to study the active biological process in animal models of renal injury (Nishihara K, et al., 2010; Mishra J et al., 2003). It is clear that every step of the inflammatory and fibrotic pathway is subject to both positive and negative regulatory events to achieve an optimal immune response (Medzhitov R et al., 2009; Ruland J et al., 2011). A new class of small noncoding RNAs, called microRNAs (miRNAs), has emerged as important regulators in the development of immune and inflammatory response (O'Connell R et al., 2012; Alam MM et al., 2011). The importance of miRNAs in the modulation of normal and pathological immune function is emerging in several studies in which deregulation of miRNAs was demonstrated to follow diseases associated with excessive or uncontrolled inflammation (Medzhitov R et al., 2009). Low level laser therapy (LLLT) is a non invasive therapy, without side effects and contraindication, with low cost. Several studies demonstrated the beneficial effect of LLLT on cardiovascular (Tomimura et al., 2014), pulmonary (de Lima FM et al., 2009-2015), acute colitis (Zigmond 2014), and kidney fibrosis (Oliveira et al., 2010). Here, we wil examine the potential contribution of in the resolution of inflammatory for the effect of LLLT on the fibrotic process. In this work, we formulate the central hypothesis that LLLT induces differentiation of kidney macrophages to a pro-resolving phenotype (anti-inflammatory), influencing the initial stages of the inflammatory microenvironment by monitoring the expression of pro resolution receptors coupled to G protein, and major signaling pathways and ligands in order to identify the signature of these pro resolution mediators in mitigating the development of fibrotic process, improving kidney function in general. For this, we will use a murine model of CKD and knockout animals FPR2 KO, MC1 KO, MC3 KO, GPR18 KO, 15 LOX KO and the epithelial cell line MM55K to induce renal injury. We will use different molecular/cellular biology techniques with focus on global expression of microRNAs to establish a pro-resolving signature involved in fibrotic process, specially evoked by LLLT. In this manner, we hope to contribute to the development of new treatments.